Safety Study of Dantrolene in Subarachnoid Hemorrhage

Subarachnoid Hemorrhage Clinical Trial

Official title:

Dantrolene in the Prevention and Treatment of Cerebral Vasospasm in Subarachnoid Hemorrhage

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01024972
• Other study ID #: H-13441
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: December 1, 2009
• Last updated: February 18, 2015
• Start date: October 2009
• Est. completion date: October 2013

Study information

• Verified date: February 2015
• Source: University of Massachusetts, Worcester
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Subarachnoid hemorrhage (SAH) is a devastating acute brain injury due to bleeding onto the brain surface from a ruptured aneurysm. Cerebral vasospasm (cVSP; critical narrowing of brain arteries) is a known complication after SAH and significantly increases disability and death after SAH. Vasospasm is difficult to treat and can lead to stroke. Animal studies have shown that the muscles in the artery wall play a role in cVSP.

Dantrolene has been FDA approved and extensively used in clinical practice as a muscle relaxant for more than 30 years. It has been shown to provide some benefit in animal studies of cVSP, as well as in a small number of humans. However, the first human studies have only been observational and over a short period of time.

This study will evaluate the safety and tolerability of intravenous dantrolene given every 6 hours over seven days to patients with or at risk for cVSP after SAH. The goal is to determine if future efficacy studies should be done to determine if treatment with Dantrolene may improve the outcome of patients with cVSP after SAH.

Description:

Once eligibility criteria are met, patients will be randomized to either dantrolene-IV or placebo (equiosmolar, volume-equivalent sterile water with 5% mannitol as dantrolene-IV also contains 5% mannitol). Study subjects will be visited daily by a study nurse to determine side effects, tolerability, record hemodynamic measures and laboratory values. Patients will have daily serum Na, osmolality, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALK) measured. In addition, daily bedside transcranial doppler will be performed by a blinded examiner. Patients will undergo cerebral angiograms per clinical routine. Angiographic measurements of arterial narrowing will be performed by a blinded radiologist. Specific stop criteria are pre-defined.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: October 2013
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Documented aneurysmal SAH by computed tomography angiography (CTA), magnetic resonance angiography (MRA) or angiography

• Secured aneurysm (coiled or clipped)

• Enrollment achievable within 14 days after SAH

Exclusion Criteria:

• Pregnancy

• Prior history of cirrhosis or hepatitis B/C, or any two of the following three liver enzymes elevated to greater than: ALT >120 Units/L, AST >120 Units/L, alkaline phosphatase >345 Units/L (three times upper limit of normal)

• Patients on verapamil

• Patients with brain edema and/or elevated intracranial pressure (>25mm Hg)

• Patients treated with hypertonic saline or mannitol prior to enrollment

• Patients with too severe SAH with low likelihood of survival (Hunt & Hess 5)

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cerebral Vasospasm
• Hemorrhage
• Subarachnoid Hemorrhage
• Vasospasm, Intracranial

Intervention

Drug:
• Dantrolene
Dantrolene 1.25mg/kg IV (includes 5% mannitol) every 6 hours x 7 days
• Placebo
equiosmolar volume (5% mannitol) every 6 hours x 7 days

Locations

Country	Name	City	State
United States	UMASS Medical School / UMass Memorial Medical Center	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
University of Massachusetts, Worcester	American Heart Association

Country where clinical trial is conducted

United States, 

References & Publications (5)

Muehlschlegel S, Carandang R, Hall W, Kini N, Izzy S, Garland B, Ouillette C, van der Bom IM, Flood TF, Gounis MJ, Weaver JP, Barton B, Wakhloo AK. Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-control — View Citation

Muehlschlegel S, Rordorf G, Bodock M, Sims JR. Dantrolene mediates vasorelaxation in cerebral vasoconstriction: a case series. Neurocrit Care. 2009;10(1):116-21. doi: 10.1007/s12028-008-9132-5. Epub 2008 Aug 12. — View Citation

Muehlschlegel S, Rordorf G, Sims J. Effects of a single dose of dantrolene in patients with cerebral vasospasm after subarachnoid hemorrhage: a prospective pilot study. Stroke. 2011 May;42(5):1301-6. doi: 10.1161/STROKEAHA.110.603159. Epub 2011 Mar 31. — View Citation

Muehlschlegel S, Sims JR. Dantrolene: mechanisms of neuroprotection and possible clinical applications in the neurointensive care unit. Neurocrit Care. 2009;10(1):103-15. doi: 10.1007/s12028-008-9133-4. Epub 2008 Aug 12. Review. — View Citation

Salomone S, Soydan G, Moskowitz MA, Sims JR. Inhibition of cerebral vasoconstriction by dantrolene and nimodipine. Neurocrit Care. 2009;10(1):93-102. doi: 10.1007/s12028-008-9153-0. Epub 2008 Oct 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hyponatremia	Number of subjects who developed hyponatremia (sNa =132mmol/L)	Seven days	Yes
Secondary	Liver Toxicity	Number of subjects who developed liver toxicity as evidenced by Liver Function Test elevation greater than 5 times the upper limit of normal.	7 days	Yes
Secondary	In-hospital Mortality	Number of subjects who expired during hospitalization.	up to 90 days	No